Tetraplatin (NSC 363812) is a new anticancer platinum drug analog targeted for clinical development because of its effectiveness against cisplatin-resistant tumor cell lines and its improved formulation. The toxicity of tetraplatin was assessed in Fischer 344 rats and compared to equimolar doses of cisplatin and CHIP (NSC 256927). This emphasis of this investigation was the comparison of the relative nephrotoxicity of these platinum analogs and the relative senstitivity of various tests used to monitor renal function. At equimolar doses tetraplatin was less nephrotoxic than cisplatin. Furthermore, the characteristics of tetraplatin occurred at the dose of tetraplatin where indication of nephrotoxicity were first detected. In contract to cisplatin, effects on proximal tubular cell function assessed in renal cortical slices were less severe. Histologically, the tetraplatin lesion extended throughout the renal cortex and no frank tubular necrosis was observed. Cisplatin lesions were characteristically localized in the cortico-medullary junction and were more severe. Urinary excretion of proteins, glucose and enzymes was the most sensitive indicator for the onset of nephrotoxicity. BUN and serum creatinine were not elevated until the renal damage was more severe at higher doses. There appear to be other differences between the toxicity of tetraplatin and cisplatin relating to hemtologic disorders and gastrointestinal toxicity.